Cephaeline promotes ferroptosis by targeting NRF2 to exert anti-lung cancer efficacy.

CONTEXT: Cephaeline is a natural product isolated from ipecac (Cephaelis ipecacuanha [Brot.] A. Rich. [Rubiaceae]). It exhibits promising anti-lung cancer activity and ferroptosis induction may be a key mechanism for its anti-lung cancer effect. OBJECTIVES: This study investigates the anti-lung cancer activity and mechanisms of cephaeline both in vitro and in vivo. MATERIALS AND METHODS: H460 and A549 lung cancer cells were used. The cephaeline inhibition rate on lung cancer cells was detected via a Cell Counting Kit-8 assay after treatment with cephaeline for 24 h. Subsequently, the concentrations of 25, 50 and 100 nM were used for in vitro experiments. In addition, the antitumour effects of cephaeline (5, 10 mg/kg) in vivo were evaluated after 12 d of cephaeline treatment. RESULTS: Cephaeline showed significant inhibitory effects on lung cancer cells, and the IC50 of cephaeline on H460 and A549 at 24, 48 and 72 h were 88, 58 and 35 nM, respectively, for H460 cells and 89, 65 and 43 nM, respectively, for A549 cells. Meanwhile, we demonstrated that ferroptosis is the key mechanism of cephaeline against lung cancer. Finally, we found that cephaeline induced ferroptosis in lung cancer cells by targeting NRF2. DISCUSSION AND CONCLUSION: We demonstrated for the first time that cephaeline inhibits NRF2, leading to ferroptosis in lung cancer cells. These findings may contribute to the development of innovative therapeutics for lung cancer.

Photocatalytic Three-Component Reaction for the Synthesis of Multifunctional Diaryl Sulfides.

A photocatalytic three-component reaction of a nitroarene, a thiophenol, and a ketone for the synthesis of multifunctional diaryl sulfides was reported using a nitro group as the nitrogen source and thiophenol as the sulfur source. Thiophenol also serves as a proton donor to reduce nitroarene to arylamine as a key intermediate for the formation of C-N and C-S bonds. Good functional group tolerance and mild reaction conditions make this method have practical synthetic value for diversified multifunctional diaryl sulfides.

Bioinspired PROTAC-induced macrophage fate determination alleviates atherosclerosis.

Atherosclerosis is a major cause of death and disability in cardiovascular disease. Atherosclerosis associated with lipid accumulation and chronic inflammation leads to plaques formation in arterial walls and luminal stenosis in carotid arteries. Current approaches such as surgery or treatment with statins encounter big challenges in curing atherosclerosis plaque. The infiltration of proinflammatory M1 macrophages plays an essential role in the occurrence and development of atherosclerosis plaque. A recent study shows that TRIM24, an E3 ubiquitin ligase of a Trim family protein, acts as a valve to inhibit the polarization of anti-inflammatory M2 macrophages, and elimination of TRIM24 opens an avenue to achieve the M2 polarization. Proteolysis-targeting chimera (PROTAC) technology has emerged as a novel tool for the selective degradation of targeting proteins. But the low bioavailability and cell specificity of PROTAC reagents hinder their applications in treating atherosclerosis plaque. In this study we constructed a type of bioinspired PROTAC by coating the PROTAC degrader (dTRIM24)-loaded PLGA nanoparticles with M2 macrophage membrane (MELT) for atherosclerosis treatment. MELT was characterized by morphology, size, and stability. MELT displayed enhanced specificity to M1 macrophages as well as acidic-responsive release of dTRIM24. After intravenous administration, MELT showed significantly improved accumulation in atherosclerotic plaque of high fat and high cholesterol diet-fed atherosclerotic (ApoE-/-) mice through binding to M1 macrophages and inducing effective and precise TRIM24 degradation, thus resulting in the polarization of M2 macrophages, which led to great reduction of plaque formation. These results suggest that MELT can be considered a potential therapeutic agent for targeting atherosclerotic plaque and alleviating atherosclerosis progression, providing an effective strategy for targeted atherosclerosis therapy.

The RNA cap methyltransferases RNMT and CMTR1 co-ordinate gene expression during neural differentiation.

Regulation of RNA cap formation has potent impacts on gene regulation, controlling which transcripts are expressed, processed and translated into protein. Recently, the RNA cap methyltransferases RNA guanine-7 methyltransferase (RNMT) and cap-specific mRNA (nucleoside-2'-O-)-methyltransferase 1 (CMTR1) have been found to be independently regulated during embryonic stem (ES) cell differentiation controlling the expression of overlapping and distinct protein families. During neural differentiation, RNMT is repressed and CMTR1 is up-regulated. RNMT promotes expression of the pluripotency-associated gene products; repression of the RNMT complex (RNMT-RAM) is required for repression of these RNAs and proteins during differentiation. The predominant RNA targets of CMTR1 encode the histones and ribosomal proteins (RPs). CMTR1 up-regulation is required to maintain the expression of histones and RPs during differentiation and to maintain DNA replication, RNA translation and cell proliferation. Thus the co-ordinate regulation of RNMT and CMTR1 is required for different aspects of ES cell differentiation. In this review, we discuss the mechanisms by which RNMT and CMTR1 are independently regulated during ES cell differentiation and explore how this influences the co-ordinated gene regulation required of emerging cell lineages.

Investigation of familial tendency of endometriosis / 中华妇产科杂志

Objective: To investigate the familial heritability of endometriosis and to compare the clinical characteristics of patients with or without a family history of endometriosis. Methods: From January 2020 to June 2022, 850 patients with endometriosis confirmed by laparotomy or laparoscopy in Peking University Third Hospital were included in this study. Clinical data were collected, family history was followed up, and the differences of clinical indicators between patients with and without family history of endometriosis were compared. Results: A total of 850 patients were enrolled, with an average age of (33.8±7.0) years old, 315 (37.1%, 315/850) patients in stage Ⅲ and 496 (58.4%, 496/850) patients in stage Ⅳ. There were 100 patients with family history of endometriosis, accounting for 11.8% (100/850). Most of the 113 relatives involved were mothers, daughters and sisters (76.1%, 86/113), 81.5% (22/27) of the second and third degree relatives were maternal relatives. The median ages of patients with and without family history of endometriosis were 30 and 33 years old respectively at the time of diagnosis. The unmarried rate of patients with family history was higher [42.0% (42/100) vs 26.3% (197/750)]. The percentage of dysmenorrhea patients with family history was higher [89.0% (89/100) vs 55.5% (416/750)]. The medians of dysmenorrhea score in patients with and without family history were 6 and 2, and the median durations of dysmenorrhea were 10 and 1 years. There were significant differences in age, marital status, percentage of dysmenorrhea, dysmenorrhea score and duration (all P<0.001). The median levels of serum cancer antigen (CA) 125 in patients with family history and patients without family history at the time of diagnosis were 57.5 and 46.9 kU/L respectively, with a statistically significant difference (P<0.05). However, there were no significant differences between the two groups in nationality, bady mass index, menarche age, menstrual cycle, menstrual period, menstrual volume, serum CA19-9 level, cyst location and size, stage, history of adverse pregnancy and childbirth, infertility, adenomyosis and deep infiltrating endometriosis (all P>0.05). By comparing the specific conditions of dysmenorrhea patients with and without family history of endometriosis, there were no significant differences between the two groups in terms of the age of onset of dysmenorrhea, duration of dysmenorrhea, primary and secondary dysmenorrhea, and progressive aggravation of dysmenorrhea (all P>0.05). The difference in the degree of dysmenorrhea in dysmenorrhea patients with family history of endometriosis was significant (P<0.001). Conclusions: The incidence of endometriosis has a familial tendency, and most of the involved relatives are the first degree relatives. Compared with patients without family history of endometriosis, endometriosis patients with family history are diagnosed at an earlier age, with higher percentage of dysmenorrhea, had more severe dysmenorrhea and higher serum CA125 level.

Recent research progress of circular RNAs in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is an extremely heterogeneous malignant tumor with a high morbidity and mortality. Circular RNAs (circRNAs) are noncoding RNAs with high stability, organ/tissue/cell-specific expression and are conserved across species. Accumulating evidence suggested that circRNAs play crucial roles as microRNA sponges, protein sponges, scaffolds, recruiters and could even polypeptide encoders. Many studies have since revealed that circRNAs were aberrantly expressed in HCC and acted as crucial modulators of HCC carcinogenesis and progression. Furthermore, circRNAs have also been identified as potential diagnostic and prognostic biomarkers for HCC. In this review, we thoroughly outline and evaluate the function of circRNAs in HCC development, with an emphasis on the specific molecular pathways by which they participated in the formation and progression of HCC, and we address their potential for serving as clinical biomarkers in HCC.

CMTR1 is recruited to transcription start sites and promotes ribosomal protein and histone gene expression in embryonic stem cells.

CMTR1 (cap methyltransferase 1) catalyses methylation of the first transcribed nucleotide of RNAPII transcripts (N1 2'-O-Me), creating part of the mammalian RNA cap structure. In addition to marking RNA as self, N1 2'-O-Me has ill-defined roles in RNA expression and translation. Here, we investigated the gene specificity of CMTR1 and its impact on RNA expression in embryonic stem cells. Using chromatin immunoprecipitation, CMTR1 was found to bind to transcription start sites (TSS) correlating with RNAPII levels, predominantly binding at histone genes and ribosomal protein (RP) genes. Repression of CMTR1 expression resulted in repression of RNAPII binding at the TSS and repression of RNA expression, particularly of histone and RP genes. In correlation with regulation of histones and RP genes, CMTR1 repression resulted in repression of translation and induction of DNA replication stress and damage. Indicating a direct role for CMTR1 in transcription, addition of recombinant CMTR1 to purified nuclei increased transcription of the histone and RP genes. CMTR1 was found to be upregulated during neural differentiation and there was an enhanced requirement for CMTR1 for gene expression and proliferation during this process. We highlight the distinct roles of the cap methyltransferases RNMT and CMTR1 in target gene expression and differentiation.

Moxibustion alleviates decreased ovarian reserve in rats by restoring the PI3K/AKT signaling pathway.

OBJECTIVE: Moxibustion, a common therapy in traditional Chinese medicine, has potential benefits for treating decreased ovarian reserve (DOR). The present study investigates the protective effect of moxibustion in a rat model of DOR and explores the possible mechanisms. METHODS: Sixty-four female Sprague-Dawley rats were randomly divided into four groups: control, DOR, moxibustion (MOX), and hormone replacement therapy (HRT). The DOR rat model was established by intragastric administration of 50 mg/kg Tripterygium glycoside suspension (TGS), once daily for 14 days. MOX and HRT treatments were given from the day TGS administration was initiated. The ovarian reserve function was evaluated by monitoring the estrus cycle, morphological changes in ovaries, levels of serum estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and anti-Mullerian hormone (AMH), pregnancy rate and embryo numbers. Terminal-deoxynucleotidyl transferase-mediated nick-end-labeling staining was used to identify ovarian granulosa cell apoptosis, while the protein and mRNA expressions of Bax, B-cell lymphoma-2 (Bcl-2), phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) in ovarian tissues were examined by immunohistochemistry, Western blot and quantitative reverse transcription-polymerase chain reaction. RESULTS: Compared with the DOR group, MOX improved the disordered estrous cycle, promoted follicular growth, reduced the number of atresia follicles, increased the concentrations of serum E2 and AMH, and decreased serum FSH and LH concentrations. More importantly, the pregnancy rate and embryo numbers in DOR rats were both upregulated in the MOX treatment group, compared to the untreated DOR model. Further, we found that the MOX group had reduced apoptosis of ovarian granulosa cells, increased Bcl-2 expression and reduced expression of Bax. Furthermore, the PI3K/AKT signaling pathway was triggered by the moxibustion treatment. CONCLUSION: Moxibustion improved ovarian function and suppressed apoptosis of ovarian granulosa cells in a rat model of DOR induced by TGS, and the mechanism may involve the PI3K/AKT signaling pathway.

Study on biological behavior of small tumor breast cancer with axillary lymph node metastasis as the first symptom / 中国医师进修杂志

Objective:To explore the biological behavior of small tumor (≤1.0 cm) breast cancer with axillary lymph node metastasis as the first symptom, and to provide a powerful reference for clinical accurate treatment.Methods:The clinical, pathological and follow-up data of 60 breast cancer patients with small tumor and axillary lymph node metastasis as the first symptom admitted to the Second Affiliated Hospital of Harbin Medical University and the Third Affiliated Hospital of Harbin Medical University from 2017 to 2019 were analyzed retrospectively (study group). Meanwhile, non-small tumor with negative lymph node (control group A), non-small tumor with positive lymph node (control group B) and small tumor with negative lymph node (control group C) were included as control groups. Selected estrogen receptor(ER), progesterone receptor(PR), human epidermal growth factor receptor-2(Her-2) and Ki67 to compare and analyze the difference between primary lesions and axillary lymph node metastasis, and made a comprehensive analysis with the follow-up data.Results:There were no statistically significant differences in the four indexes in primary lymph nodes and metastatic lymph nodes between the study group and the control group ( P>0.05). The expression of HER-2 in control group B, study group, control group C, control group A showed a decreasing trend. In the study group, there were 19 cases with >3 axillary lymph node metastasis, the positive rate of HER-2 was 11/19, and 37 cases with 3 lymph node metastasis, the positive rate of HER-2 was 21.6%(8/37), the difference was statistically significant ( P<0.05), but there was no significant difference in the expression of ER, PR and Ki67 ( P>0.05). In control group B, there was no significant difference between the groups with >3 axillary lymph node metastasis and 3 groups ( P>0.05). Combined with the follow-up data, in the study group with >3 lymph node metastasis, there were 4 cases with distant metastasis and Ki67 expression rate was 4/4, while there were 13 cases with no distant metastasis and Ki67 expression rate was 5/13, the difference was statistically significant ( P<0.05). Conclusions:The expressions of ER, PR, Her-2 and Ki67 in primary breast cancer including small tumor and axillary lymph node metastasis are consistent. In most cases, the overall condition can be evaluated by biological indicators of primary disease, but some patients do have inconsistencies, which should arouse the attention of clinicians for comprehensive condition evaluation. Her-2 positive expression seems to be related to axillary lymph node metastasis as a whole, especially in small tumor breast cancer with T≤1.0 cm. For patients with axillary lymph node metastasis and invasive ductal carcinoma with primary lesion ≤1.0 cm, the high expression of Ki67 seems to indicate that distant metastasis is more likely to occur in the longer term.

Study on anti-Parkinson's disease activity of Eucommia ulmoides based on network pharmacology and zebrafish model / 中国药理学通报

Aim To investigate anrl further verify the anti-PD activity and underlying mechanism of Eucom¬mia ulmoides and based on network pharmacological methods and zebrafish Parkinson's disease ( PD) mod¬el.Methods The DISGENET database and TCMSP database were used to screen the active components, key targets of Eucommia ulmoides and PD related tar¬gets.The network diagram of active components-tar- gets-PD was drawn.The protein interaction network di¬agram was constnicted.GO enrichment analysis and KEGG pathway enrichment analysis were performed.Hie behavioral detection was verified by and quantita¬tive real-time PCR (qRT-PCR) based on zebrafish PD model.Results The network pharmacological study screened the potential targets associated with anti-PD action of Eucommia ulmoides.Protein-protein interac¬tion network ( PPI) analysis showed that there was tight interaction among thees targets.GO and KEGG enrichment analysis showed that Eucommia ulmoides could regulate the levels of PD neurotransmitter and the activity of dopamine neurotransmitter receptor, in¬volved in dopaminergic synapses and other related sig¬naling pathways.In vivo zebrafish PD model experi¬ments confirmed the anti-PD activity of Eucommia ul¬moides, which was related to the regulation of dopam¬inergic nervous system.Conclusions The anti-PD activity, active components, and potential targets of Eucommia ulmoides are revealed in this study.In vivo experiments verified that Eucommia ulmoides can alle¬viate PD-like symptoms in zebrafish, and it also reveals that Eucommia ulmoides exert anti-PD activity by regu¬lating dopaminergic nervous system.

Real-world outcomes in locally advanced or metastatic urothelial carcinoma following platinum and PD-1/L1 inhibitor therapy.

Aim: To investigate real-world overall survival (rwOS) and real-world progression-free survival (rwPFS) in locally advanced/metastatic urothelial carcinoma postplatinum and postprogrammed death receptor-1/death ligand 1 inhibitors. Patients & methods: Adult patients diagnosed with locally advanced/metastatic urothelial carcinoma from 1 January 2011 to 31 December 2018 and treated with taxane monotherapy or any therapy postplatinum and post-PD-1/L1 inhibitors were included from a nationwide electronic health record-derived oncology database. Results: Median rwOS among 72 patients treated with taxane monotherapy was 7.6 months (95% CI: 5.2-14.4) and rwPFS was 2.9 months (95% CI: 2.4-4.0). Among 208 patients treated with any therapy, median rwOS was 8.9 months (95% CI: 7.3-10.6) and rwPFS was 3.6 months (95% CI: 2.7-4.7). Conclusion: Short duration of rwOS and rwPFS were observed, highlighting the need for effective and safe treatments in this patient population.

Lay abstract Few studies have evaluated survival outcomes in patients with advanced urothelial cancer who have disease relapse after chemotherapy and PD-1/L1 inhibitor therapy in clinical practice. In this study, we used electronic health records from a nationwide cancer database to assess survival in adult patients who received further treatment in this setting from 2011 to 2018. Among 72 patients who were treated with taxane monotherapy after chemotherapy and a PD-1/L1 inhibitor, average overall survival was 7.6 months and progression-free survival was 2.9 months. Among 208 patients who were treated with any therapy, average overall survival was 8.9 months and progression-free survival was 3.6 months. These results highlight the need for safer and more effective therapies in patients with advanced urothelial cancer who have disease relapse after chemotherapy and PD-1/L1 inhibitor therapy.

Moxibustion Ameliorates Ovarian Reserve in Rats by Mediating Nrf2/HO-1/NLRP3 Anti-Inflammatory Pathway.

Diminished ovarian reserve (DOR) is an increasingly emerging reproductive disorder that disturbs reproductive-aged women, which is closely linked with inflammation. In clinic, moxibustion has already been applied for reproductive problems. In the present study, we examined the involvement of inflammation in DOR and investigated the effect of moxibustion for its anti-inflammatory activities. Methods. DOR rat model was established using tripterygium glycosides A tablets (TGs) suspension by intragastric administration and was then treated with either moxibustion or hormone replacement therapy (HRT), respectively. Estrus cycles were observed through vaginal cytology. Ovarian morphological alterations were observed by HE staining. The serum levels of follicle-stimulating hormone (FSH), estradiol (E 2), anti-Müllerian hormone (AMH), tumor necrosis factor alpha (TNF-α), and interleukin-10 (IL-10) were measured through ELISA. The expression levels of Nrf2, HO-1, and NLRP3 were detected using immunohistochemistry. Nrf2, HO-1, and NLRP3 mRNA were examined by RT-PCR. Results. Moxibustion improved estrus cycles, FSH, E 2, and AMH levels relative to DOR rats as well as HRT, while also inhibiting ovarian tissue injury. Anti-inflammatory cytokine IL-10 in peripheral blood was upregulated, and proinflammatory factor TNF-α was decreased after treatment with moxibustion. Moxibustion enhanced the expression of mRNA and protein of nuclear factor erythroid 2-related factor (Nrf2) and heme oxygenase-1 (HO-1); in the mean time, nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) was suppressed. Conclusions. We demonstrated that moxibustion could ameliorate the ovarian reserve in rats induced by TGs. Overall, the effect of moxibustion was comparable to that of HRT. The underlying mechanism could be attributed to the anti-inflammatory effects of moxibustion, which suppressed NLRP3 activation by upregulating Nrf2/HO-1 signaling pathway.

Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV­201): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Locally advanced or metastatic urothelial carcinoma is generally incurable and has scarce treatment options, especially for cisplatin-ineligible patients previously treated with PD-1 or PD-L1 therapy. Enfortumab vedotin is an antibody-drug conjugate directed at Nectin-4, a protein highly expressed in urothelial carcinoma. We aimed to evaluate the efficacy and safety of enfortumab vedotin in the post-immunotherapy setting in cisplatin-ineligible patients. METHODS: EV-201 is a multicentre, single-arm, phase 2 study of enfortumab vedotin in patients with locally advanced or metastatic urothelial carcinoma previously treated with PD-1 or PD-L1 inhibitors. Cohort 2 included adults (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status score of 2 or less who were considered ineligible for cisplatin at enrolment and who had not received platinum-containing chemotherapy in the locally advanced or metastatic setting. Enfortumab vedotin was given intravenously at a dose of 1·25 mg/kg on days 1, 8, and 15 of every 28-day cycle. The primary endpoint was confirmed objective response rate per Response Evaluation Criteria in Solid Tumours version 1.1 assessed by blinded independent central review. Efficacy and safety were analysed in all patients who received at least one dose of enfortumab vedotin. EV-201 is an ongoing study and the primary analysis is complete. This study is registered with Clinicaltrials.gov, NCT03219333. FINDINGS: Between Oct 8, 2017, and Feb 11, 2020, 91 patients were enrolled at 40 sites globally, of whom 89 received treatment. Median follow-up was 13·4 months (IQR 11·3-18·9). At data cutoff (Sept 8, 2020), the confirmed objective response rate was 52% (46 of 89 patients; 95% CI 41-62), with 18 (20%) of 89 patients achieving a complete response and 28 (31%) achieving a partial response. 49 (55%) of 89 patients had grade 3 or worse treatment-related adverse events. The most common grade 3 or 4 treatment-related adverse events were neutropenia (eight [9%] patients), maculopapular rash (seven [8%] patients), and fatigue (six [7%] patients). Treatment-related serious adverse events occurred in 15 (17%) patients. Three (3%) patients died due to acute kidney injury, metabolic acidosis, and multiple organ dysfunction syndrome (one [1%] each) within 30 days of first dose and these deaths were considered by the investigator to be related to treatment; a fourth death from pneumonitis occurred more than 30 days after the last dose and was also considered to be related to treatment. INTERPRETATION: Treatment with enfortumab vedotin was tolerable and confirmed responses were seen in 52% of cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma who were previously treated with PD-1 or PD-L1 inhibitors. These patients have few treatment options, and enfortumab vedotin could be a promising new therapy for a patient population with a high unmet need. FUNDING: Astellas Pharma Global Development and Seagen.

The phenotypic and genetic spectrum of colony-stimulating factor 1 receptor gene-related leukoencephalopathy in China / 中华神经科杂志

Objective:To summarize and analyze the clinical data of Chinese patients with colony-stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy, and clarify the phenotypic and genetic characteristics of Chinese patients.Methods:Medical history of patients with CSF1R-related leukoencephalopathy diagnosed from April 1, 2018 to January 31, 2021 in the department of neurology of 22 hospitals in China was collected, and scores of Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment Scale (MoCA), magnetic resonance severity scale were evaluated. Group comparison was performed between male and female patients.Results:A total of 62 patients were included, and the male-female ratio was 1∶1.95. The age of onset was (40.35±8.42) years. Cognitive impairment (82.3%, 51/62) and motor symptoms (77.4%,48/62) were the most common symptoms. The MMSE and MoCA scores were 18.79±7.16 and 13.96±7.23, respectively, and the scores of two scales in male patients (22.06±5.31 and 18.08±5.60) were significantly higher than those in females (15.53±7.41 , t=2.954, P=0.006; 10.15±6.26, t=3.328 , P=0.003). The most common radiographic feature was bilateral asymmetric white matter changes (100.0%), and the magnetic resonance imaging severity scale score was 27.42±11.40, while the white matter lesion score of females (22.94±8.39) was significantly higher than that of males (17.62±8.74 , t=-2.221, P<0.05). A total of 36 CSF1R gene mutations were found in this study, among which c.2381T>C/p.I794T was the hotspot mutation that carried by 17.9% (10/56) of the probands. Conclusions:The core phenotypic characteristics of CSF1R-related leukoencephalopathy in China are progressive motor and cognitive impairment, with bilateral asymmetrical white matter changes. In addition, there exist gender differences clinically, with severer cognitive impairment and imaging changes in female patients. Thirty-six CSF1R gene mutations were found in this study, and c.2381T>C/p. I794T was the hotspot mutation.

Choice and consideration of digestive tract reconstruction after total gastrectomy and proximal gastrectomy / 中华消化外科杂志

At present, the surgical treatment of upper gastric cancer, including esophago-gastric junction cancer, mainly includes the total gastrectomy and proximal gastrectomy. After total gastrectomy, the reconstruction of digestive tract is completed through the anastomosis of esophagus and jejunum. Patients undergoing total gastrectomy often face the risk of poor eating effect and malnutrition. Compared with total gastrectomy, the proximal gastrectomy can preserve part of the gastric tissue, but due to the loss of the normal physiological structure of the cardia, patients have a higher risk of postoperative reflux. In order to solve the problem of reflux, there are many improved operation methods of digestive tract reconstruction after proximal gastrectomy. At present, the choice of total gastrectomy or proximal gastrectomy and the operation methods of digestive tract reconstruction is still controversial. Because of the lack of sufficient theoretical research support. The authors comb the research progress and consider the concept and method of digestive tract reconstruction after total gastrectomy and proximal gastrectomy, in order to provide theoretical basis for clinical work.

A novel collision tumour of myofibroblastoma and low-grade adenosquamous carcinoma in breast.

BACKGROUND: Myofibroblastoma (MFB) and low-grade adenosquamous carcinoma (LGASC) are rare tumours in the breast, respectively. However, a collision tumour of the two types has never been reported. CASE PRESENTATION: A 42-year-old female presented with a palpable mass in diameter of about 2.5 cm in the left breast. Morphologically, the lesion was predominately composed of bland spindle cells admixed with some islands of mature adipocytes and a few epithelial elements dispersing in infiltrating way which formed both tubule and solid structures. The mass showed low positive index of Ki-67. The spindle cells were strongly and diffusely positive for CD34, SMA, desmin, ER and PR. The epithelial elements were positive for CK and EMA, and negative for ER and PR completely. CK5/6 and P63 were positive in the outer-layer of the tubules and nearly all the cells of the solid nests. CONCLUSIONS: A collision tumour of MFB and LGASC in breast is extremely rare and either component is supposed to be not overlooked. Excision and close follow-up are advised.

Involvement of PaSNF1 in Fungal Development, Sterigmatocystin Biosynthesis, and Lignocellulosic Degradation in the Filamentous Fungus Podospora anserina.

The sucrose non-fermenting 1/AMP-activated protein kinase (SNF1/AMPK) is a central regulator of carbon metabolism and energy production in the eukaryotes. In this study, the functions of the Podospora anserina SNF1 (PaSNF1) ortholog were investigated. The ΔPaSNF1 mutant displays a delayed development of mycelium and fruiting bodies and fails to form ascospores. The expression of the PaSNF1 gene in the strain providing female organs in a cross is sufficient to ensure fertility, indicating a maternal effect. Results of environmental stress showed that ΔPaSNF1 was hypersensitive to stress, such as osmotic pressure and heat shock, and resistant to fluconazole. Interestingly, the knockout of PaSNF1 significantly promoted sterigmatocystin (ST) synthesis but suppressed cellulase [filter paperase (FPA), endoglucanase (EG), and ß-glucosidase (BG)] activity. Further, transcriptome analysis indicated that PaSNF1 made positive regulatory effects on the expression of genes encoding cellulolytic enzymes. These results suggested that PaSNF1 may function in balancing the operation of primary and secondary metabolism. This study suggested that SNF1 was a key regulator concerting vegetative growth, sexual development, and stress tolerance. Our study provided the first genetic evidence that SNF1 was involved in the ST biosynthesis and that it may also be a major actor of lignocellulose degradation in P. anserina.

Compounds of traditional Chinese medicine and neuropathic pain.

Neuropathic pain (NP) has become a serious global health issue and a huge clinical challenge without available effective treatment. P2 receptors family is involved in pain transmission and represents a promising target for pharmacological intervention. Traditional Chinese medicine (TCM) contains multiple components which are effective in targeting different pathological mechanisms involved in NP. Different from traditional analgesics, which target a single pathway, TCMs take the advantage of multiple components and multiple targets, and can significantly improve the efficacy of treatment and contribute to the prediction of the risks of NP. Compounds of TCM acting at nucleotide P2 receptors in neurons and glial cells could be considered as a potential research direction for moderating neuropathic pain. This review summarized the recently published data and highlighted several TCMs that relieved NP by acting at P2 receptors.

Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy.

PURPOSE: Locally advanced or metastatic urothelial carcinoma is an incurable disease with limited treatment options, especially for patients who were previously treated with platinum and anti-programmed death 1 or anti-programmed death ligand 1 (PD-1/L1) therapy. Enfortumab vedotin is an antibody-drug conjugate that targets Nectin-4, which is highly expressed in urothelial carcinoma. METHODS: EV-201 is a global, phase II, single-arm study of enfortumab vedotin 1.25 mg/kg (intravenously on days 1, 8, and 15 of every 28-day cycle) in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum chemotherapy and anti-PD-1/L1 therapy. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by blinded independent central review. Key secondary end points were duration of response, progression-free survival, overall survival, safety, and tolerability. RESULTS: Enfortumab vedotin was administered to 125 patients with metastatic urothelial carcinoma. Median follow-up was 10.2 months (range, 0.5 to 16.5 months). Confirmed objective response rate was 44% (95% CI, 35.1% to 53.2%), including 12% complete responses. Similar responses were observed in prespecified subgroups, such as those patients with liver metastases and those with no response to prior anti-PD-1/L1 therapy. Median duration of response was 7.6 months (range, 0.95 to 11.30+ months). The most common treatment-related adverse events were fatigue (50%), any peripheral neuropathy (50%), alopecia (49%), any rash (48%), decreased appetite (44%), and dysgeusia (40%). No single treatment-related adverse events grade 3 or greater occurred in 10% or more of patients. CONCLUSION: Enfortumab vedotin demonstrated a clinically meaningful response rate with a manageable and tolerable safety profile in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum and anti-PD-1/L1 therapies.

Novel DPY19L2 variants in globozoospermic patients and the overcoming this male infertility / 亚洲男科学杂志(英文版)

Globozoospermia has been reported to be a rare but severe causation of male infertility, which results from the failure of acrosome biogenesis and sperm head shaping. Variants of dpy-19-like 2 (DPY19L2) are highly related to globozoospermia, but related investigations have been mainly performed in patients from Western countries. Here, we performed a screening of DPY19L2 variants in a cohort of Chinese globozoospermic patients and found that five of nine patients carried DPY19L2 deletions and the other four patients contained novel DPY19L2 point mutations, as revealed by whole-exome sequencing. Patient 3 (P3) contained a heterozygous variant (c.2126+5G>A), P6 contained a homozygous nonsense mutation (c.1720C>T, p.Arg574*), P8 contained compound heterozygous variants (c.1182-1184delATC, p.Leu394_Ser395delinsPhe; c.368A>T, p.His123Arg), and P9 contained a heterozygous variant (c.1182-1184delATCTT, frameshift). We also reported intracytoplasmic sperm injection (ICSI) outcomes in the related patients, finding that ICSI followed by assisted oocyte activation (AOA) with calcium ionophore achieved high rates of live births. In summary, the infertility of these patients results from DPY19L2 dysfunction and can be treated by ICSI together with AOA.